Low Tumor Mutation Levels Improve Response to Immunotherapy in Recurrent Glioblastoma

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Glioblastoma brain cancer, CT scan
Glioblastoma brain cancer. Coloured computed tomography (CT) scan of a section through the brain of an 84-year-old female patient with glioblastoma (dark, top). Glioblastoma is the most aggressive form of brain cancer.

Having a low level of tumor mutation improves immunotherapy treatment response and survival time in patients with recurrent glioblastoma, suggests research led by Duke University.

The team hopes this insight could help clinicians target immunotherapy better to tumors most likely to respond.

An interesting finding from the study was that this improved response was only seen in patients with recurrent tumors and not those with newly diagnosed disease, suggesting that something happens to the patient’s immune response during initial treatment.

“This suggests that chemotherapy, which is the standard of care for newly diagnosed glioblastoma, might be altering the inflammatory response in these tumors,” said David Ashley, M.D., Ph.D., a professor at Duke University School of Medicine who led the research.

Glioblastoma has a poor prognosis and is often fatal. It also has an almost 100% recurrence rate, despite early, aggressive chemotherapy treatments.

However, some recent trials of immunotherapy treatments have shown that 10-20% of patients with recurrent tumors do respond well to treatment and survive significantly longer than other patients with the aggressive brain cancer.

“We’ve had some success with several different immunotherapies, including the poliovirus therapy developed at Duke,” noted Ashley.

In some other cancers, tumors with higher levels of mutations have proved more difficult to treat than those with lower levels. To investigate if this is true for recurrent glioblastoma, Ashley and colleagues carried out genomic analysis on recurrent glioblastoma tumor samples taken before treatment with recombinant polio virotherapy or immune checkpoint blockade and compared them with samples from newly diagnosed patients with the brain cancer.

As reported in the journal Nature Communications, a common finding was that recurrent patients with low tumor mutation burden responded best to either treatment. They had survival times of more than 20 months compared with a median survival of around 12 months for all recurrent glioblastoma patients.

Notably, a link between tumor mutation burden and treatment response was not seen in glioblastoma patients who were being treated for the first time. When the team compared tumor samples from these patients with those in the recurrent group who had low numbers of tumor mutations they found that samples from recurrent patients had higher levels of inflammation-association gene expression.

“Together these findings imply that increased survival of immunotherapy-treated glioblastoma patients with very low tumor mutation burden is due to immunotherapy response,” write the authors. In other words, the higher level of inflammation in these tumors makes them more susceptible to treatment with immunotherapy.

The researchers now plan to validate their results in further studies and also to investigate how initial chemotherapy treatment might change immune-related gene expression in the tumors and assess if this happens in other cancers.

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